Combinatorial (hybrid) Ia antigenic determinants are generated by gene complementations in both the cis- and trans-positions. At least three Ia determinants (Ia.21,22,23) associated with the I-E subregion are believed to be combinatorial Ia determinants generated by specific AEpsilonEAlpha molecular configuration. Recent evidence suggests that Ia.22 may not be one unique determinant but rather a family of cross-reacting determinants. This proposal outlines strategies to be utilized in the production of monoclonal antibodies and T-cell clones specific for combinatorial Ia determinants associated with both the I-A and I-E subregions. Through the use of monoclonal antibodies, serological and biochemical date will be obtained related to the monecular basis of combinatorial Ia determinants. The serological data in conjuction with cellular data collected from panel testing in proliferation assays would provide a foundation and basis for splitting of a combinatorial determinant into families of related, but not unique, determinants. From these investigations an understanding of the molecular basis for Ia antigenic deeterminants might be forthcoming. In addition, insights into the mechanisms of Ia antigen associated-Ir gene function would be possible.